A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8-21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre-and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.S erotonin (5-HT) has long been postulated to play a trophic role in brain morphogenesis, including cell proliferation, migration, and differentiation. It is also known to be one of the first neurotransmitters to appear in the central nervous system (1, 2). An obvious question that can be raised relates to whether perinatal exposure to antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can affect cortical circuit development and function. Perhaps one of the most intriguing previous findings related to 5-HT and early cortical organization was the observation from immunohistochemical and 5-HT transporter (SERT) binding studies that, at postnatal days 2-14 (P2-P14), rodent primary sensory cortex (notably layer IV of visual, auditory, and somatosensory areas) is transiently innervated by aggregates of fine grainlooking 5-HT-containing processes (3)(4)(5). Surprisingly, it became clear that, in early brain development, 5-HT is taken up into glutamatergic thalamocortical terminals (6, 7) and used in combination with the 5-HT 1B receptor on layer IV afferents (8). At present, the functional implication of such transient 5-HT expression and targeting, namely the primary sensory thalamocortical afferents during early development, remains unknown.5-HT and Abnormal Brain Development. Interestingly, manipulations of rodent brain 5-HT levels during early development, either through increases (produced in SERT or monoamine oxidase knockout mice) or decreases (produced by parachlorophenylalanine or other treatments), have been shown to produce the downstream effect of interfering with the formation of the whisker (barrel) representation in the primary somatosensory cortex and promoting aggressive and/or anxiety-related behaviors (9-14). Furthermore, early-life modification of 5-HT levels has been shown to cause overreaction to auditory or tactile sensory stimulation (15) and abnormal response properties of cor...

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